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Critical molecular determinants for activation of calcium flux into cells revealed

May 31, 2017

Triggered by decreases in ER Ca2+ level, conformational changes of the endoplasmic reticulum (ER) luminal domain in STIM1 would switch on its cytoplasmic domain (CT) to engage and gate ORAI channels on plasma membrane, resulting in Ca2+ influx. This so-called store-operated Ca2+ entry (SOCE) process mediates a series of important Ca2+-dependent cellular activities in mammals. Dysregulated SOCE is known to cause immune and muscle disorders. However, "the activation mechanism of SOCE remains to be fully characterized." says the lead study author Dr. Yubin Zhou, an associate professor at the Center for Translational Cancer Research, Institute of Biosciences and Technology at Texas A&M University. "We developed a real-time cellular assay designed to monitor STIM1 rest and activation status. This assay provides a platform for us to re-evaluate the roles of STIM1 major functional domains in maintaining a quiescent configuration of STIM1." More explanations added by the first author Dr. Guolin Ma.

Researchers from Texas A&M University and Beijing Normal University have gained new insights into factors crucial for the activation of STIM1. The study, published in Current Molecular Medicine (PMID: 28231751) with the title "Molecular determinants for STIM1 activation during store-operated Ca2+ entry", reveals how the transmembrane (TM), first coiled-coil (CC1) and other cytosolic domains of STIM1 is required for controlling the calcium entry into mammalian cells.

Dr. Yubin Zhou's and Dr. Youjun Wang's teams replaced the TM domain of STIM1 by a more rigid dimerized TM domain, and found that STIM1 activation was abolished. This adverse effect could be partially reversed by disrupting the TM dimerization interface. That means "structural flexibility of TM domain is essential for STIM1 transmitting signals" says Dr. Wang. They then tested the ability of STIM1 cytosolic fragments to interact with its ER-spanning fragments and further examined effects of such interactions on STIM1 activation. Their results indicate that, the minimal STIM1-Orai1 activating Region, SOAR, has to be exposed to drive further oligomerization and activation of STIM1 molecules. This study forms a solid foundation for ongoing efforts to develop potential therapeutics by targeting aberrant STIM-ORAI signaling to treat immunoinflammatory diseases and muscle disorders.
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Bentham Science Publishers

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